(1) Field of the Invention
This invention concerns an improved method for manufacturing a therapeutic tablet that dissolves nearly instantaneously upon contact with water. This method improves upon traditional freeze-dry methods which include preparing an aqueous suspension containing a granular therapeutic agent, placing the aqueous suspension in molds, and freeze drying the aqueous suspension to produce a solid pharmaceutic tablet. The improved method of this invention incorporates a particular agent into the aqueous gelatin containing suspension in order to keep the granular therapeutic agent uniformly dispersed, but does so without degrading the speed of dissolution or the texture and "feel" of the tablet upon dissolution in the mouth.
(2) Description of the Art
Many pharmaceutical dosage forms are administered orally in the form of solid, shaped articles such as tablets, pills, and capsules that retain their shape under moderate pressure. Generally these dosage forms are designed to be swallowed whole, chewed, or retained sublingually or bucally in order to deliver the medication. Some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. To assist these patients, therapeutic compounds are sometimes provided as a liquid or suspension. However, these dosage forms are often difficult to distribute and store due to problems with stability. Other patients may not have water available at the time that they should take medication, and patient compliance is accordingly reduced. Still other patients resist taking medication, and may try to hide a solid pill in order to spit it out later.
The prior art discloses methods for manufacturing therapeutic tablets that immediately dissolve on contact with saliva in the mouth. Many of these prior art manufacturing methods involve freeze drying aqueous drug formulations. U.S. Pat. No. 4,371,516, discloses shaped articles, carrying pharmaceuticals, which disintegrate rapidly in the mouth. The shaped articles comprise an open matrix of carrier material, interspersed with the medicament. The articles may be prepared by subliming solvent from a composition comprising the medicament and the carrier material in solution, the solution being in a solid state in the mold.
This unique dosage form provides a solid tablet means for delivering medicaments which disintegrates on the tongue of a patient within 10 seconds or less. This rapid tablet disintegration rate makes the dosage form suitable for patients who have difficulty swallowing or refuse to swallow conventional tablets containing such medicaments. Further, the dosage form is exceptionally convenient since it does not require the aid of water in order to be swallowed. As such, the rapidly disintegrating nature of the dosage form and the convenience associated with its use offer dramatic improvement in patient compliance and treatment of disease states.
U.S. Pat. No. 4,305,502, discloses packages containing shaped articles carrying chemicals, particularly dosage forms carrying pharmaceuticals. The shaped articles, which disintegrate rapidly in saliva, are contained in depressions in sheets of filmic material and are enclosed by a covering sheet adhering to the filmic material. The shaped articles may be formed in the depressions by a sublimation process.
U.S. Pat. No. 4,758,598, discloses the preparation of solid shaped articles, particularly pharmaceutical dosage forms, by freezing a composition comprising a predetermined amount of chemical (e.g., a pharmaceutically active compound) and a carrier material solution in a mold, and then subliming solvent from the frozen composition. The side wall or walls of the mold are angled to minimize sublimation times.
U.S. Pat. No. 4,754,597 discloses the preparation of solid shaped articles, particularly rapidly dissolving pharmaceutical dosage forms. The articles carry predetermined unit quantities of chemicals and are made by a novel process involving the addition of the predetermined amount of chemical to a solid sublimed carrier article, prepared by freeze drying a carrier solution.
U.S. Pat. No. 5,188,825 discloses a freeze-dried dosage form that is prepared from a solution including a bulk forming agent and a therapeutic agent containing ion exchange resin having a particle size less than 90 microns. The bulk forming agent may be gelatin or xanthan gum. The bulk forming agent is added to the solution to maintain the dispersion of the active agent/ion exchange resin combination.
U.S. Pat. No. 5,206,025 discloses a porous pharmaceutical form and its method of preparation. The porous pharmaceutical form is prepared by freeze drying a solution including an active substance, binders, diluents, and additives. The binder includes xanthan gum, and gelatin in amounts to yield colloidal solutions.
U.S. Pat. No. 5,272,137 discloses an aqueous pharmaceutical suspension including microcrystalline cellulose and xanthan gum. The solution formed is capable of forming a suspension of particles ranging in size from 1 to about 850 microns.
Although these prior art freeze dried dosage forms offer many advantages over hard pills and capsules, the prior art dosage forms are limited in certain respects. For example, the prior art freeze dried dosage form were limited when used with medicaments that had both relatively low solubility in water and relatively large particle size. In such situations, the medicament tended to separate out of suspension too quickly during the manufacturing process, thereby forming an undesirable layer of sediment at the bottom of the tablet. Although the suspension could be extended by use of various thickening agents, these agents tended to degrade the dissolution characteristics of the tablet in the mouth.